Jang Eun Jeong, Kim Heejeong, Baek Seung Eun, Jeon Eun Yeong, Kim Ji Won, Kim Ju Yeon, Kim Chi Dae
Department of Pharmacology, School of Medicine, Pusan National University, Yangsan 50612, Korea.
Department of Laboratory Medicine, Pusan National University Hospital, Busan 49241, Korea.
Korean J Physiol Pharmacol. 2022 Sep 1;26(5):389-396. doi: 10.4196/kjpp.2022.26.5.389.
The increased expression of receptors for advanced glycation end-product (RAGE) is known as a key player in the progression of vascular remodeling. However, the precise signal pathways regulating RAGE expression in vascular smooth muscle cells (VSMCs) in the injured vasculatures are unclear. Given the importance of mitogen-activated protein kinase (MAPK) signaling in cell proliferation, we investigated the importance of MAPK signaling in high-mobility group box 1 (HMGB1)-induced RAGE expression in VSMCs. In HMGB1 (100 ng/ml)-stimulated human VSMCs, the expression of RAGE mRNA and protein was increased in association with an increase in AGE-induced VSMC proliferation. The HMGB1-induced RAGE expression was attenuated in cells pretreated with inhibitors for ERK (PD98059, 10 μM) and p38 MAPK (SB203580, 10 μM) as well as in cells deficient in ERK and p38 MAPK using siRNAs, but not in cells deficient of JNK signaling. In cells stimulated with HMGB1, the phosphorylation of ERK, JNK, and p38 MAPK was increased. This increase in ERK and p38 MAPK phosphorylation was inhibited by p38 MAPK and ERK inhibitors, respectively, but not by JNK inhibitor. Moreover, AGE-induced VSMC proliferation in HMGB1-stimulated cells was attenuated in cells treated with ERK and p38 MAPK inhibitors. Taken together, our results indicate that ERK and p38 MAPK signaling are involved in RAGE expression in HMGB1-stimulated VSMCs. Thus, the ERK/p38 MAPK-RAGE signaling axis in VSMCs was suggested as a potential therapeutic target for vascular remodeling in the injured vasculatures.
晚期糖基化终产物受体（RAGE）表达增加是血管重塑进展中的关键因素。然而，在受损血管中调节血管平滑肌细胞（VSMC）中RAGE表达的精确信号通路尚不清楚。鉴于丝裂原活化蛋白激酶（MAPK）信号在细胞增殖中的重要性，我们研究了MAPK信号在高迁移率族蛋白B1（HMGB1）诱导的VSMC中RAGE表达中的重要性。在HMGB1（100 ng/ml）刺激的人VSMC中，RAGE mRNA和蛋白的表达增加，同时AGE诱导的VSMC增殖也增加。在用ERK抑制剂（PD98059，10 μM）和p38 MAPK抑制剂（SB203580，10 μM）预处理的细胞中，以及使用小干扰RNA（siRNA）使ERK和p38 MAPK缺陷的细胞中，HMGB1诱导的RAGE表达减弱，但在JNK信号缺陷的细胞中则没有减弱。在用HMGB1刺激的细胞中，ERK、JNK和p38 MAPK的磷酸化增加。ERK和p38 MAPK磷酸化的这种增加分别被p38 MAPK和ERK抑制剂抑制，但不被JNK抑制剂抑制。此外，在用ERK和p38 MAPK抑制剂处理的细胞中，HMGB1刺激的细胞中AGE诱导的VSMC增殖减弱。综上所述，我们的结果表明ERK和p38 MAPK信号参与了HMGB1刺激的VSMC中RAGE的表达。因此，VSMC中的ERK/p38 MAPK-RAGE信号轴被认为是受损血管中血管重塑的潜在治疗靶点。
